Cell Res︱Li Dan/Wang Jian/Liu Cong collaborated to discover and characterize novel pathological protein fibril aggregates formed by TMEM106B in human brain

Written by Fan Yun and Editor Wang Sizhen The protein fiber aggregates formed by pathological proteins through liquid-solid phase transition are important pathological markers of various neurodegenerative diseases (NDs)[1]
.

Pathological aggregates formed by different proteins have been found in different NDs to have a variety of different pathological toxicities, including: activation of neuroinflammation, disruption of protein homeostasis, induction of mitochondrial damage, and spread across brain regions and organs [2-5] ]
.

Therefore, the study of the structure, aggregation mechanism and pathological toxicity of pathological protein aggregates is of great significance for understanding the pathogenic mechanism of NDs and drug development
.

 On April 27, 2022, Li Dan's research group from Shanghai Jiao Tong University, Wang Jian's research group from Huashan Hospital Affiliated to Fudan University, and Liu Cong's research group from Shanghai Institute of Organic Chemistry jointly published an online publication in Cell Research entitled "Generic amyloid fibrillation of TMEM106B in patient with Parkinson's disease dementia and normal elders"
.

In this study, researchers discovered a previously unknown novel pathological protein aggregation directly from the brain tissue of a Parkinson's disease dementia (PDD) patient with dementia and two elderly healthy controls.
It was further revealed by cryo-electron microscopy and mass spectrometry that this new protein pathological aggregate was formed by the transmembrane protein 106B (transmembrane protein 106B, TMEM106B) folded into a novel curling sheet structural unit and further self-assembled
.

This work discovered a new class of pathological protein fibril aggregates in the brains of ND patients and healthy elderly people, and discussed the role of the newly discovered protein aggregates in NDs and aging
.

Li Dan and Liu Cong's research group have cooperated for a long time to study the molecular mechanism of liquid-solid phase transition and aggregation of α-syn, a key protein in Parkinson's disease, and develop new methods for chemical intervention
.

Previous studies mainly rely on α-syn protein aggregates prepared in vitro [6,7]
.

In this work, the two research groups worked closely with Wang Jian's research group from Huashan Hospital to try to directly extract α-syn pathological protein aggregates from the brain tissue of PDD patients, and successfully extract protein fibers from the brain tissue through multi-step purification.
aggregates (Figure 1)
.

Surprisingly, however, protein fibril aggregates extracted from PDD brain tissue were not formed by α-syn
.

Further, the researchers identified this brand-new protein aggregate by cryo-electron microscopy and mass spectrometry and other techniques
.

Fig.
1 Extraction method and results of protein fiber aggregates in human brain tissue
.

(Source: Fan Y, et al.
, Cell Res, 2022) What’s more interesting is that in addition to the brain tissue of PDD patients, the researchers also extracted the brain tissue of two other elderly healthy controls to obtain the same TMEM106B formed.
protein fiber aggregates
.

Further studies found that TMEM106B formed a novel curling conformation different from its native conformation in PDD and two healthy control brain tissues and assembled into fiber aggregates with a similar β-sheet structure
.

However, TMEM106B has subtle differences in the three different sources of fiber aggregates
.

In healthy control No.
2, TMEM106B presented a Type 1 structure composed of single-strand fibrils (Fig.
2); in healthy control No.
1, it was a Type 2 structure composed of single-strand fibrils; in PDD, TMEM106B with both structures coexisted Fibers, one with the same Type 2 structure as the healthy control No.
1, and the other with the Type 3 structure consisting of two fibrils with the same structure as Type 2
.

Both Type 1 and Type 2 fiber aggregates consisted of the C-terminal domain (residue 120–254) of TEME106B, forming a curling-like configuration containing 17 β-sheets (Fig.
2)
.

Figure 2 Cryo-EM structure of TMEM106B fiber aggregates in brain tissue of PDD patients and aged healthy controls
.

(Source: Fan Y, et al.
, Cell Res, 2022) It is worth mentioning that in the past month or so, the Fitzpatrick research group at Columbia University, the Eisenberg research group at the University of California, Los Angeles, and the Goedert & Scheres research group at the University of Cambridge The group has successively reported research results highly related to this study in Cell and Nature[8-10]
.

Among them, the research group of Fitzpatrick and Eisenberg obtained TMEM106B pathological fiber aggregates from the brains of patients with different types of NDs (including frontotemporal lobar degeneration, progressive supranuclear palsy, dementia with Lewy bodies, etc.
), and believed that the aggregates formed by TMEM106B It is closely related to the onset of different NDs, especially frontotemporal lobar degeneration
.

However, the Goedert & Scheres research group found that TMEM106B exists not only in the brain tissue of ND patients, but also in the brain tissue of elderly healthy people, and speculated that the TMEM106B aggregate may be an aging-related age-dependent protein aggregate, which is not directly related to the pathogenesis of NDs.
association
.

Therefore, the above three works have great controversy on the pathological significance of TMEM106B fibrous aggregates
.

 In this work, the researchers comprehensively analyzed the age distribution characteristics of brain tissue donors used to extract TMEM106B fiber aggregates reported in this work and the above three works in different subgroups, and found that whether familial or sporadic The age of NDs patients was significantly lower than that of healthy controls (Fig.
3)
.

Accordingly, disease and age together are proposed as two key drivers for the formation of pathological fibrous aggregates in TMEM106B
.

Figure 3.
Statistical analysis of age of brain tissue donors containing TMEM106B fibers
.

(Image source: Fan Y, et al.
, Cell Res, 2022) Conclusion and discussion, inspiration and prospect of the article In conclusion, this research work unexpectedly discovered a new class of TMEM106B proteins from the midbrain tissue of PDD patients and elderly healthy controls.
protein, and the atomic structure of TMEM106B fibers was analyzed by cryo-electron microscopy helical remodeling; in addition, this study comprehensively analyzed three recently published studies with conflicting conclusions and the brain tissue donors in this study.
According to the age distribution characteristics, it was found that the formation of TMEM106B fibers is directly related to disease and aging
.

This work provides new insights for understanding the complex role of different protein pathological aggregates in disease and aging; it opens up new ideas for further exploring the complex pathological and physiological activities of different protein aggregates in the human brain; This presents new challenges for the development of PET tracers that identify pathological protein aggregates
.

There has been little attention and related research on TMEM106B protein before.
In future research, not only the normal physiological function of TMEM106B protein needs to be further revealed, but also the formation mechanism of TMEM106B amyloid fibrils and its relationship with the occurrence and development of neurodegenerative diseases need to be further explored
.

Link to the original text: https:// Fan Yun, a graduate student of Huashan Hospital Affiliated to Fudan University, Zhao Qinyue, a graduate student of Shanghai Jiaotong University, and Xia Wencheng, a graduate student of the Interdisciplinary Center of the Shanghai Institute of Organic Chemistry, are the authors of the paper.
Co-first author
.

This work is heavily funded by the Fund Committee, the Ministry of Science and Technology and the Shanghai Municipal Science and Technology Commission
.

Corresponding author Li Dan (left), corresponding author Wang Jian (right) (Photo provided by: Li Dan/Wang Jian/Liu Cong team) Corresponding author/laboratory profile and recruitment information (swipe up and down to read) Li Dan: Ph.
D.
, Shanghai Special researcher, research group leader and doctoral supervisor of Jiaotong University
.

Dr.
Li Dan focuses on protein phase separation and phase transition, and develops cutting-edge technologies such as cryo-electron microscopy-based electron diffraction, helical fiber imaging, in-cell nuclear magnetic resonance, etc.
The atomic molecular basis of neurodegenerative diseases
.

In the past 5 years, he has published a number of scientific research results in high-level journals such as Cell, Nature sub-journals, PNAS, and Cell Research
.

 Wang Jian: Doctor, professor/chief physician, doctoral supervisor
.

Deputy Director of the Department of Neurology, Huashan Hospital, Director of the National Clinical Research Center for Geriatric Diseases (Huashan) "Neurodegenerative Diseases" Research, Director of the Geriatric Cognitive and Movement Disorder Research Center of the "Geriatrics and Health Research Institute" of Fudan University
.

Long-term focus on PD clinical and basic research, long-term management of chronic diseases, published 106 SCI papers, cited 2802 times, H index 31 (Google Scholar)
.

In the past 5 years, as the correspondent/first author, he has published 48 papers focusing on Parkinson's disease (7 of which are >10 points)
.

Presided over a total of 7 major (cultivation), general, youth projects and other National Natural Science Foundation of China, and presided over the sub-project of "Parkinson's Disease Molecular Imaging Research" key project of the Ministry of Science and Technology's National Key R&D Program "Research on the Prevention and Control of Major Chronic Non-Infectious Diseases" And a number of provincial and ministerial-level topics
.

 Postdoctoral and Technician Recruitment Li Dan's research group of Shanghai Jiaotong University and Liu Cong's research group of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences are looking for outstanding talents (including postdoctoral fellows and technicians) to join the team to explore protein phase transitions and pathological aggregation in neurodegenerative diseases Pathological mechanism of action in the chemistry-biology-medicine research paradigm, and develop new strategies for small molecule-based chemical intervention and early clinical diagnosis of diseases
.

The research team will provide good scientific research development opportunities and superior treatment
.

Interested applicants please contact: liulab@sioc.
ac.
cn The Wang Jian research group of Huashan Hospital Affiliated to Fudan University is looking for a super postdoctoral fellow of Fudan University to join the team to conduct neuroimaging and pathogenesis of Parkinson's disease and related neurodegenerative diseases , clinical and basic research for early diagnosis and modification therapy
.

The research group will provide good scientific research development opportunities and favorable treatment.
Interested applicants please contact: hspdworkshop@163.
com
.

 Talent recruitment[1] "Logical Neuroscience" is looking for an associate editor/editor/operation position (online office) Selected articles from previous issues[1] Neuron︱Chen Tao/Li Yunqing/Zhuo Min's research group cooperates to reveal the synaptic and Molecular mechanism【2】Transl Psychiatry︱Li Yan/Zhang Jie’s team used transcutaneous electrical acupoint stimulation for the first time in the treatment of attention deficit hyperactivity disorder in school-age children【3】Aging Cell Review︱Zhang Hong/Chen Yingzhi/Tian Mei Collaborative Review of Intestines The mechanism by which flora regulates the function of microglia and participates in cognitive aging【4】Review of Front Cell Neurosci︱Microglia: the hub of intercellular communication in ischemic stroke【5】Review of Trends Neurosci︱Circadian clock and blood glucose metabolism Rhythm research progress【6】Front Aging Neurosci︱Sun Tao’s research group proposes a new protocol for 11C-PiB-PET imaging for early diagnosis of Alzheimer’s disease Double-edged sword effect in vascular units 【8】HBM︱Region-based brain MRI spatial standardization method to achieve accurate registration of brain regions【9】J Neuroinflammation︱Peng Ying’s group revealed that microglia mitophagy plays an important role in The regulatory role of morphine-induced central nervous system inflammatory inhibition [10] Curr Biol︱ Novelty detection and the relationship between surprise and recency in the primate brain Recommended for high-quality scientific research training courses [1] Patch clamp and optogenetics and calcium Imaging Technology Symposium May 21-22 Tencent Conference References (swipe up and down to read) 1Goedert, M.
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Plate making︱Sizhen Wang End of this paper1038/s41586-022-04650-z (2022).
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Plate making︱Sizhen Wang End of this paper